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The multi\u2010omics and spontaneous model findings indicate that lactate accumulation in the tumor microenvironment (TME) promotes histone H3 lysine 18 lactylation (H3K18la) and activation of cancer\u2010associated fibroblasts (CAFs), leading to both ECM densification and impaired immunotherapy efficacy in PDAC. Mechanistically, ubiquitin\u2010conjugating enzyme E2T (UBE2T) acts as an initiating factor that promotes p53 positive feedback degradation through modulation of ribosome biogenesis, thereby enhancing lactate metabolic crosstalk via glycolytic reprogramming. Genetic ablation or pharmacological inhibition of UBE2T using the selective inhibitor pentagalloylglucose (PGG) disrupts lactate metabolic crosstalk, suppresses stromal deposition, and promotes intratumoral CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells infiltration. Furthermore, the combination of PGG and anti\u2010PD\u20101 therapy exhibits synergistic effects and survival benefits in spontaneous PDAC mice and immune\u2010reconstituted patient\u2010derived xenografts. Collectively, these findings reveal that UBE2T drives p53 positive feedback degradation to enhance glycolysis of PDAC, leading to excessive lactate production, which promotes H3K18la in CAFs and subsequent ECM deposition. Targeting UBE2T represents a potential strategy to improve the efficacy of immunotherapy in PDAC.\n                  <\/jats:p>","DOI":"10.1002\/advs.202514933","type":"journal-article","created":{"date-parts":[[2026,2,15]],"date-time":"2026-02-15T11:47:26Z","timestamp":1771156046000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["UBE2T\u2010Driven p53 Degradation Rewires Glycolysis to Orchestrate Lactylation\u2010Mediated CAFs Activation and ECM Deposition in Pancreatic Cancer"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5323-9320","authenticated-orcid":false,"given":"Yong","family":"Ma","sequence":"first","affiliation":[{"name":"The Second Hospital &amp; Clinical Medical School Lanzhou University  Lanzhou China"},{"name":"Department of General Surgery Lanzhou University Second Hospital  Lanzhou China"},{"name":"Gansu Tumor Immunology Basic Disciplines Research Center The 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